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Trial record 2 of 13 for:    AG-348

A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03692052
Recruitment Status : Active, not recruiting
First Posted : October 2, 2018
Last Update Posted : March 12, 2020
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE September 10, 2018
First Posted Date  ICMJE October 2, 2018
Last Update Posted Date March 12, 2020
Actual Study Start Date  ICMJE December 28, 2018
Estimated Primary Completion Date September 13, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 28, 2018)
Percentage of Participants Achieving a Hemoglobin Response (HR) [ Time Frame: Up to 12 weeks ]
HR is defined as a ≥1.0 gram per deciliter (g/dL) increase in Hb concentration from baseline at 1 or more assessments between Week 4 and Week 12 (inclusive). A participant's baseline Hb concentration is defined as the average of all the participant's available Hb concentrations during the 42-day screening period up to the first dose of study drug.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 24, 2019)
  • Mean Change from Baseline in Hb Concentrations from Week 12 to Week 24 [ Time Frame: Baseline, Week 12 to Week 24 ]
  • Percentage of Participants Achieving a Sustained Hb Response (sHR) [ Time Frame: Week 12 to Week 24 ]
    sHR is defined as achieving HR and achieving a ≥1.0 g/dL increase in Hb concentration at 2 or more evaluable Hb assessments out of the 4 scheduled assessments between the Week 12 Visit and Week 24 Visit
  • Percentage of Participants Achieving a Delayed Hb Response [ Time Frame: Week 12 to Week 24 ]
    Delayed Hb response is defined as not achieving HR and achieving a ≥1.0 g/dL increase in Hb concentration at 1 or more Hb assessments after Week 12.
  • Change from Baseline in Hb Concentration over an Additional 2 Years in the Extension Period [ Time Frame: Baseline up to approximately 2.5 years ]
  • Time to First ≥1.0 g/dL Increase in Hb Concentration [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Reticulocyte Count [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Bilirubin [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Lactate Dehydrogenase (LDH) [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Haptoglobin [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Nucleated Red Blood Cells (NRBCs) [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Erythropoietin (EPO) [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Soluble Transferrin Receptor [ Time Frame: Up to approximately 2.5 years ]
  • Drug Concentrations over Time for AG-348 [ Time Frame: Pre-dose at Weeks 2, 4, 6, 8, 16, 20, and 24 ]
  • Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), and AEs Leading to Study Drug Dose Reduction, Study Drug Interruption, and Study Drug Discontinuation [ Time Frame: Up to approximately 2.5 years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 28, 2018)
  • Mean Change from Baseline in Hb Concentrations from Week 12 to Week 24 [ Time Frame: Baseline, Week 12 to Week 24 ]
  • Percentage of Participants Achieving a Sustained Hb Response (sHR) [ Time Frame: Week 12 to Week 24 ]
    sHR is defined as a ≥1.0 g/dL increase in Hb concentration at 2 or more evaluable Hb assessments out of the 4 scheduled assessments between the Week 12 Visit and Week 24 Visit
  • Change from Baseline in Hb Concentration over an Additional 2 Years in the Extension Period [ Time Frame: Baseline up to approximately 2.5 years ]
  • Time to Achieve HR [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Reticulocyte Count [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Bilirubin [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Lactate Dehydrogenase (LDH) [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Haptoglobin [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Nucleated Red Blood Cells (NRBCs) [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Erythropoietin (EPO) [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Soluble Transferrin Receptor [ Time Frame: Up to approximately 2.5 years ]
  • Change from Baseline in Iron [ Time Frame: Up to Week 120 ]
  • Change from Baseline in Serum Ferritin [ Time Frame: Up to Week 120 ]
  • Change from Baseline in Total Iron-binding Capacity (TIBC) [ Time Frame: Up to Week 120 ]
  • Change from Baseline in Transferrin Saturation [ Time Frame: Up to Week 120 ]
  • Change from Baseline in Hepcidin [ Time Frame: Up to Week 120 ]
  • Change from Baseline in C-reactive Protein [ Time Frame: Up to Week 120 ]
  • Drug Concentrations over Time for AG-348 [ Time Frame: Pre-dose at Weeks 1, 2, 3, 4, 6, 8, 16, 20, and 24 ]
  • Change from Baseline in Adenosine Triphosphate (ATP) Concentrations [ Time Frame: Pre-dose on Day 1 and at Weeks 6, 8, 12, and 24 ]
  • Change from Baseline in 2,3-DPG Concentrations [ Time Frame: Pre-dose on Day 1 and at Weeks 6, 8, 12, and 24 ]
  • Change from Baseline in Red Blood Cell (RBC)-specific Form of Pyruvate Kinase (PKR) Activity [ Time Frame: Pre-dose and at 2 hours post-dose on Day 1; pre-dose at Week 12 ]
  • Change from Baseline in PKR Protein Levels [ Time Frame: Pre-dose on Day 1 and at Weeks 12 and 24 ]
  • Change from Baseline in PKR Flux Assay Results [ Time Frame: Pre-dose on Day 1 and at Week 12 ]
  • Percentage of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Significant Interest (AESIs), and AEs Leading to Study Drug Dose Reduction, Study Drug Interruption, and Study Drug Discontinuation [ Time Frame: Up to approximately 2.5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia
Official Title  ICMJE A Phase 2, Open-label, Multicenter Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Subjects With Non-transfusion-dependent Thalassemia
Brief Summary Study AG348-C-010 is a multicenter study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of treatment with AG-348 in adult participants with non-transfusion-dependent thalassemia (NTDT). This study will include a 24-week core period followed by a 2-year extension period for eligible participants. Approximately 17 participants with NTDT will be enrolled. The initial dose of AG-348 will be 50 milligrams (mg) twice daily (BID) with one potential dose-level increase to 100 mg BID, at the Week 6 visit based on the participant's safety and hemoglobin (Hb) concentrations.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Thalassemia
Intervention  ICMJE Drug: AG-348

Core period: Participants will receive an initial AG-348 dose of 50 mg BID, oral tablets, and may undergo one potential dose-level increase to 100 mg BID, based on an evaluation of the participant's safety profile and Hb concentrations.

Extension Period: Participants who achieve a Hb response with an acceptable safety profile will continue receiving treatment with AG-348 for up to 2 years at the same dose they were receiving at the Week 24 Visit.

Study Arms  ICMJE Experimental: AG-348

Core period: Participants will receive AG-348 for up to 24 weeks. Depending on the safety observations and hemoglobin (Hb) concentrations, they may undergo one potential dose-level increase from 50 to 100 mg BID.

Extension Period: Eligible participants will continue to receive AG-348 for up to 2 years at the same dose they were receiving at the Week 24 visit.

Intervention: Drug: AG-348
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 28, 2018)
17
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 13, 2022
Estimated Primary Completion Date September 13, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Informed consent;
  • Known medical history of thalassemia, including β-thalassemia intermedia, Hb E β-thalassemia, α-thalassemia (Hb H disease), or β-thalassemia with mutations of 1 or more α genes;
  • Documented clinical laboratory confirmation of thalassemia by Hb electrophoresis/high-performance liquid chromatography (HPLC) or deoxyribonucleic acid (DNA) analysis, either from medical records or during the screening period;
  • Hb concentration ≤10.0 grams per deciliter (g/dL), regardless of sex, based on an average of at least 2 Hb measurements (separated by a minimum of 7 days) during the screening period;
  • Considered non-transfusion-dependent, defined as having no more than 5 units of red blood cells (RBCs) transfused during the 24-week period up to the first day of study drug and no RBC transfusions in the 8 weeks prior to the first day of study drug;
  • Have adequate organ function;
  • For women of reproductive potential: negative serum pregnancy test during the screening period and a negative serum or urine pregnancy test on Day 1;
  • For women of reproductive potential as well as men with partners who are women of reproductive potential: be abstinent as part of their usual lifestyle, or agreement to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days following the last dose of study drug for women and 90 days following the last dose of study drug for men;
  • Willingness to comply with all study procedures for the duration of the study;

Exclusion Criteria:

  • Known history of diagnosis of Hb S or Hb C forms of thalassemia;
  • Significant medical condition that confers an unacceptable risk to participating in the study, and/or could confound the interpretation of the study data;
  • Splenectomy scheduled during the study treatment period or having undergone splenectomy within 12 months prior to signing informed consent;
  • Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo;
  • Exposure to any investigational drug, device, or procedure within 3 months prior to the first day of study drug;
  • Prior exposure to sotatercept (ACE-011), luspatercept (ACE-536), ruxolitinib, or gene therapy;
  • Prior bone marrow or stem cell transplant;
  • Currently pregnant or breastfeeding;
  • History of major surgery within 6 months of signing informed consent;
  • Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first day of study drug;
  • Currently receiving chronic anticoagulant therapy, unless started and on a stable dose for at least 28 days prior to first day of study drug;
  • Currently receiving anabolic steroids, including testosterone preparations, if initiated ≤28 days prior to the first day of study drug;
  • Currently receiving hematopoietic stimulating agents (e.g., erythropoietins, granulocyte colony stimulating factors, thrombopoietins), if initiated ≤8 weeks prior to the first day of study drug;
  • History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug-induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations;
  • History of allergy to AG-348 or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03692052
Other Study ID Numbers  ICMJE AG348-C-010
2018‐002217‐35 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Agios Pharmaceuticals, Inc.
Study Sponsor  ICMJE Agios Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Medical Affairs Agios Pharmaceuticals, Inc.
PRS Account Agios Pharmaceuticals, Inc.
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP